Synergistic and Multidimensional Regulation of Plasminogen Activator Inhibitor Type 1 Expression by Transforming Growth Factor Type beta and Epidermal Growth Factor

TitleSynergistic and Multidimensional Regulation of Plasminogen Activator Inhibitor Type 1 Expression by Transforming Growth Factor Type beta and Epidermal Growth Factor
Publication TypeJournal Article
Year of Publication2012
AuthorsSong XL, Thalacker FW, Nilsen-Hamilton M
Journal TitleJournal of Biological Chemistry
Volume287
Pages12520-12528
Date Published04
Type of ArticleArticle
ISBN Number0021-9258
Accession NumberWOS:000302782200091
KeywordsENDOTHELIAL-CELLS, factor increases, factor-alpha, GENE-EXPRESSION, human, messenger-rna stability, pai-1, protein, tgf-beta, thymic epithelial-cells, transcription
Abstract

The major physiological inhibitor of plasminogen activator, type I plasminogen activator inhibitor (PAI-1), controls blood clotting and tissue remodeling events that involve cell migration. Transforming growth factor type beta (TGF beta) and epidermal growth factor (EGF) interact synergistically to increase PAI-1 mRNA and protein levels in human HepG2 and mink Mv1Lu cells. Other growth factors that activate tyrosine kinase receptors can substitute for EGF. EGF and TGF beta regulate PAI-1 by synergistically activating transcription, which is further amplified by a decrease in the rate of mRNA degradation, the latter being regulated only by EGF. The combined effect of transcriptional activation and mRNA stabilization results in a rapid 2-order of magnitude increase in the level of PAI-1. TGF beta also increases the sensitivity of the cells to EGF, thereby recruiting the cooperation of EGF at lower than normally effective concentrations. The contribution of EGF to the regulation of PAI-1 involves the MAPK pathway, and the synergistic interface with the TGF beta pathway is downstream of MEK1/2 and involves phosphorylation of neither ERK1/2 nor Smad2/3. Synergism requires the presence of both Smad and AP-1 recognition sites in the promoter. This work demonstrates the existence of a multidimensional cellular mechanism by which EGF and TGF beta are able to promote large and rapid changes in PAI-1 expression.

URL<Go to ISI>://WOS:000302782200091
DOI10.1074/jbc.M111.338079
Alternate JournalJ. Biol. Chem.